Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy.

Ultrahigh dose-rate (FLASH) radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity. However, tumor recurrence largely impede the effectiveness of FLASH therapy. Overcoming tumor recurrence is crucial for practical FLASH applications. Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839). Within nanoparticles, TPE-BBT exhibits aggregation-induced emission peaked at 900 nm, while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability. The balanced photothermal effect and photoluminescence are ideal for phototheranostics. Upon 660-nm laser irradiation, the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy, jointly inhibiting homologous recombination repair of DNA. The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.

Ferritin-nanocaged aggregation-induced emission nanoaggregates for NIR-II fluorescence-guided noninvasive, controllable male contraception.

Controllable contraception in male animals was demonstrated through the utilization of gold nanorods' photothermal effect to accomplish mild testicular hyperthermia. However, the challenges arising from testicular administration and the non-biodegradability of nanoparticles hinder further clinical implementation. Therefore, a straightforward, non-invasive, and enhanced contraception approach is required. This study explores the utilization of human heavy chain ferritin (HFn) nanocarriers loaded with aggregation-induced emission luminogens (AIEgens) for noninvasive, controllable male contraception guided by Near-Infrared-II (NIR-II) fluorescence imaging. The HFn-caged AIEgens (HFn@BBT) are delivered via intravenous injection and activated by near-infrared irradiation. Lower hyperthermia treatment induces partial damage to the testes and seminiferous tubules, reducing fertility indices by approximately 100% on the 7th day, which gradually recovers to 80% on the 60th day. Conversely, implementation of elevated hyperthermia therapy causes total destruction of both testes and seminiferous tubules, leading to a complete loss of fertility on the 60th day. Additionally, the use of AIEgens in NIR-II imaging offers improved fluorescence efficiency and penetration depth. The findings of this study hold significant promise for the advancement of safe and effective male contraceptive methods, addressing the need for noninvasive and controllable approaches to reproductive health and population control.

AIEgen-deep: Deep learning of single AIEgen-imaging pattern for cancer cell discrimination and preclinical diagnosis.

This study introduces AIEgen-Deep, an innovative classification program combining AIEgen fluorescent dyes, deep learning algorithms, and the Segment Anything Model (SAM) for accurate cancer cell identification. Our approach significantly reduces manual annotation efforts by 80%-90%. AIEgen-Deep demonstrates remarkable accuracy in recognizing cancer cell morphology, achieving a 75.9% accuracy rate across 26,693 images of eight different cell types. In binary classifications of healthy versus cancerous cells, it shows enhanced performance with an accuracy of 88.3% and a recall rate of 79.9%. The model effectively distinguishes between healthy cells (fibroblast and WBC) and various cancer cells (breast, bladder, and mesothelial), with accuracies of 89.0%, 88.6%, and 83.1%, respectively. Our method's broad applicability across different cancer types is anticipated to significantly contribute to early cancer detection and improve patient survival rates.

Innovative methodology for comprehensive utilization of arsenic-bearing neutralization sludge.

Arsenic-bearing neutralization (ABN) sludge is a classical hazardous waste commonly found in nonferrous metallurgy. However, the current storage of these hazardous wastes not only has to pay costly hazardous waste taxes but also poses significant risks to both the environment and human health. To address these issues and achieve the comprehensive utilization and minimization of ABN sludge, this study proposes a new combined process. The process involves selective reduction roasting, leaching, and carbonation, through which, the arsenate and gypsum in the ABN sludge were recovered in the form of As(s), high-purity CaCO3, and H2S. The selective reduction behaviors of arsenate and gypsum were investigated through thermodynamic analysis and roasting experiments. The results indicated that the 95.35 % arsenate and 96.55 % gypsum in the sludge were selectively reduced to As4(g) and CaS at 950 °C by carbothermic reduction. The As4(g) was condensed to As(s) and enriched in the dust (As, 96.78 wt %). In the leaching process, H2S gas was adopted to promote the leaching of CaS, and resulted in 97.41 % of CaS in the roasted product was selectively leached in the form of Ca(HS)2, leading to a 74.11 % reduction in the weight of the ABN sludge. Then, the Ca(HS)2 was subjected to capture CO2 for the separation of Ca2+ and S2-. The result depicted that 99.69 % of Ca2+ and 99.12 % of S2- were separated as high-purity (99.12 wt %) CaCO3 and H2S (24.89 vol %) by controlling the terminal carbonation pH to below 6.55. The generated H2S can be economically converted to sulfur by the Clause process. The whole process realized the comprehensive resource recovery and the minimization of the sludge, which provides an alternative solution for the clean treatment of hazardous ABN waste.

Biomimetic Nano-Cancer Stem Cell Scavenger for Inhibition of Breast Cancer Recurrence and Metastasis after FLASH-Radiotherapy.

Compared to conventional radiotherapy (RT), FLASH-RT delivers ultra-high dose radiation, significantly reducing damage to normal tissue while guaranteeing the effect of cancer treatment. However, cancer recurrence and metastasis frequently occur after all RT due to the existence of intractable cancer stem cells (CSCs). To address this, a biomimetic nanoplatform (named TAFL) of tumor-derived exosome fusion liposomes is designed by co-loading aggregation-induced emission photothermal agents, TPE-BBT, and anti-cancer drugs, aspirin, aiming to clear CSCs for inhibiting cancer recurrence and metastasis after FLASH-RT therapy . Aspirin released in TAFL system triggered by laser irradiation can induce apoptosis and DNA damage of 4T1 CSCs, comprehensively downregulate their stemness phenotype, and inhibit their sphericity. Furthermore, the TPE-BBT mediated mild-photothermal therapy can alleviate the hypoxic tumor microenvironment, inhibit the DNA repair of CSCs, which further amplifies the effect of aspirin against CSCs, therefore reduces the effective dose of aspirin, making TAFL more biologically safe. In vivo experimental results demonstrated that decreased CSCs population mediated by TAFL system treatment significantly inhibited tumor recurrence and metastasis after FLASH-RT therapy. In summary, this TAFL system   provides a new idea for the future clinical application of FLASH-RT therapy.

Research Progress of Self-Healing Polymer for Ultraviolet-Curing Three-Dimensional Printing.

Ultraviolet (UV)-curing technology as a photopolymerization technology has received widespread attention due to its advantages of high efficiency, wide adaptability, and environmental friendliness. Ultraviolet-based 3D printing technology has been widely used in the printing of thermosetting materials, but the permanent covalent cross-linked networks of thermosetting materials which are used in this method make it hard to recover the damage caused by the printing process through reprocessing, which reduces the service life of the material. Therefore, introducing dynamic bonds into UV-curable polymer materials might be a brilliant choice which can enable the material to conduct self-healing, and thus meet the needs of practical applications. The present review first introduces photosensitive resins utilizing dynamic bonds, followed by a summary of various types of dynamic bonds approaches. We also analyze the advantages/disadvantages of diverse UV-curable self-healing polymers with different polymeric structures, and outline future development trends in this field.

State-dependent memory retrieval: insights from neural dynamics and behavioral perspectives.

Memory retrieval is strikingly susceptible to external states (environment) and internal states (mood states and alcohol), yet we know little about the underlying mechanisms. We examined how internally generated states influence successful memory retrieval using the functional magnetic resonance imaging (fMRI) of laboratory mice during memory retrieval. Mice exhibited a strong tendency to perform memory retrieval correctly only in the reinstated mammillary body-inhibited state, in which mice were trained to discriminate auditory stimuli in go/no-go tasks. fMRI revealed that distinct auditory cues engaged differential brain regions, which were primed by internal state. Specifically, a cue associated with a reward activated the lateral amygdala, while a cue signaling no reward predominantly activated the postsubiculum. Modifying these internal states significantly altered the neural activity balance between these regions. Optogenetic inhibition of those regions in the precue period blocked the retrieval of type-specific memories. Our findings suggest that memory retrieval is under the control of two interrelated neural circuits underlying the neural basis of state-dependent memory retrieval.

Photothermal-Triggered Sulfur Oxide Gas Therapy Augments Type I Photodynamic Therapy for Potentiating Cancer Stem Cell Ablation and Inhibiting Radioresistant Tumor Recurrence.

Despite advances in cancer therapy, the existence of self-renewing cancer stem cells (CSC) can lead to tumor recurrence and radiation resistance, resulting in treatment failure and high mortality in patients. To address this issue, a near-infrared (NIR) laser-induced synergistic therapeutic platform has been developed by incorporating aggregation-induced emission (AIE)-active phototheranostic agents and sulfur dioxide (SO2 ) prodrug into a biocompatible hydrogel, namely TBH, to suppress malignant CSC growth. Outstanding hydroxyl radical (·OH) generation and photothermal effect of the AIE phototheranostic agent actualizes Type I photodynamic therapy (PDT) and photothermal therapy through 660 nm NIR laser irradiation. Meanwhile, a large amount of SO2 is released from the SO2 prodrug in thermo-sensitive TBH gel, which depletes upregulated glutathione in CSC and consequentially promotes ·OH generation for PDT enhancement. Thus, the resulting TBH hydrogel can diminish CSC under 660 nm laser irradiation and finally restrain tumor recurrence after radiotherapy (RT). In comparison, the tumor in the mice that were only treated with RT relapsed rapidly. These findings reveal a double-boosting ·OH generation protocol, and the synergistic combination of AIE-mediated PDT and gas therapy provides a novel strategy for inhibiting CSC growth and cancer recurrence after RT, which presents great potential for clinical treatment.

Insights into the mechanisms involved in the fungal degradation of plastics.

Fungi are considered among the most efficient microbial degraders of plastics, as they produce salient enzymes and can survive on recalcitrant compounds with limited nutrients. In recent years, studies have reported numerous species of fungi that can degrade different types of plastics, yet there remain many gaps in our understanding of the processes involved in biodegradation. In addition, many unknowns need to be resolved regarding the fungal enzymes responsible for plastic fragmentation and the regulatory mechanisms which fungi use to hydrolyse, assimilate and mineralize synthetic plastics. This review aims to detail the main methods used in plastic hydrolysis by fungi, key enzymatic and molecular mechanisms, chemical agents that enhance the enzymatic breakdown of plastics, and viable industrial applications. Considering that polymers such as lignin, bioplastics, phenolics, and other petroleum-based compounds exhibit closely related characteristics in terms of hydrophobicity and structure, and are degraded by similar fungal enzymes as plastics, we have reasoned that genes that have been reported to regulate the biodegradation of these compounds or their homologs could equally be involved in the regulation of plastic degrading enzymes in fungi. Thus, this review highlights and provides insight into some of the most likely regulatory mechanisms by which fungi degrade plastics, target enzymes, genes, and transcription factors involved in the process, as well as key limitations to industrial upscaling of plastic biodegradation and biological approaches that can be employed to overcome these challenges.

Tailoring the Amphiphilic Structure of Zwitterionic AIE Photosensitizers to Boost Antitumor Immunity.

Although photodynamic therapy (PDT) for thorough cancer treatment is hindered by the limited generation of reactive oxygen species (ROS) with short lifetime from photosensitizers, PDT-induced antitumor immune response remedies the defects. Previous studies show that inducing immunogenic cell deaths is an attractive approach to activate antitumor immunity, which confers a robust adjuvanticity to dying cancer cells. In this work, amphiphilic luminogens with aggregation-induced emission characteristics (AIEgens) are rationally designed and synthesized. By modulating the hydrophobic π-bridge and zwitterionic functional groups, these AIEgens exhibit tunable organelle specificity to lysosome, endoplasmic reticulum, and plasma membrane and enhance ROS generation ability. Notably, the membrane-targeting AIEgen namely TPS-2 induces cell death and membrane rupture via PDT to facilitate the release of antigens and activation of immune cells. Furthermore, the size-controlled TPS-2 nanoaggregates are found to serve as an adjuvant, promoting antigen accumulation and delivery to sufficiently boost the in vivo antitumor immunity by only one dose injection in a prophylactic tumor vaccination model. This work thus provides new insights into optimizing AIE photosensitizers via a hydrophobicity-hydrophilicity balance strategy for evoking an antitumor immunity and directly suppressing the distanced tumor. A single small-molecular system for PDT-stimulated antitumor immunity is envisioned.

Type-I AIE Photosensitizer Loaded Biomimetic System Boosting Cuproptosis to Inhibit Breast Cancer Metastasis and Rechallenge.

Cuproptosis shows good application prospects in tumor therapy. However, the copper efflux mechanism and highly expressed intracellular reducing substances can inhibit the cuproptosis effects. In this study, a platelet vesicle (PV) coated cuprous oxide nanoparticle (Cu2O)/TBP-2 cuproptosis sensitization system (PTC) was constructed for multiple induction of tumor cuproptosis. PTC was prepared by physical extrusion of AIE photosensitizer (TBP-2), Cu2O, and PV. After the biomimetic modification, PTC can enhance its long-term blood circulation and tumor targeting ability. Subsequently, PTC was rapidly degraded to release copper ions under acid conditions and hydrogen peroxides in tumor cells. Then, under light irradiation, TBP-2 quickly enters the cell membrane and generates hydroxyl radicals to consume glutathione and inhibit copper efflux. Accumulated copper can cause lipoylated protein aggregation and iron-sulfur protein loss, which result in proteotoxic stress and ultimately cuproptosis. PTC treatment can target and induce cuproptosis in tumor cells in vitro and in vivo, significantly inhibit lung metastasis of breast cancer, increase the number of central memory T cells in peripheral blood, and prevent tumor rechallenge. It provides an idea for the design of nanomedicine based on cuproptosis.

AIEgens/Mitochondria Nanohybrids as Bioactive Microwave Sensitizers for Non-Thermal Microwave Cancer Therapy.

Aggregation-induced emission luminogens (AIEgens) are widely used as photosensitizers for image-guided photodynamic therapy (PDT). Due to the limited penetration depth of light in biological tissues, the treatments of deep-seated tumors by visible-light-sensitized aggregation-induced emission (AIE) photosensitizers are severely hampered. Microwave dynamic therapy attracts much attention because microwave irradiation can penetrate very deep tissues and sensitize the photosensitizers to generate reactive oxygen species (ROS). In this work, a mitochondrial-targeting AIEgen (DCPy) is integrated with living mitochondria to form a bioactive AIE nanohybrid. This nanohybrid can not only generate ROS under microwave irradiation to induce apoptosis of deep-seated cancer cells but also reprogram the metabolism pathway of cancer cells through retrieving oxidative phosphorylation (OXPHOS) instead of glycolysis to enhance the efficiency of microwave dynamic therapy. This work demonstrates an effective strategy to integrate synthetic AIEgens and natural living organelles, which would inspire more researchers to develop advanced bioactive nanohybrids for cancer synergistic therapy.

A type I AIE photosensitiser-loaded biomimetic nanosystem allowing precise depletion of cancer stem cells and prevention of cancer recurrence after radiotherapy.

Radioresistance of Cancer stem cell (CSC) is an important cause of tumor recurrence after radiotherapy (RT). Herein, we designed a type I aggregation-induced emission (AIE) photosensitiser-loaded biomimetic mesoporous organosilicon nanosystem (PMT) for precise depletion of CSC to prevent tumor recurrence after RT. This PMT system is composed of a type I AIE photosensitiser (TBP-2) loaded mesoporous organosilicon nanoparticles (MON) with an outer platelet membrane. The PMT system is able to specifically target CSC. Intracellular glutathione activity leads to MON degradation and the release of TBP-2. Type I photodynamic therapy is activated by exposure to white light, producing a large amount of hydroxyl radicals to promote CSC death. The results of in vivo experiments demonstrated specific removal of CSC following PMT treatment, with no tumor recurrence observed when combined with RT. However, tumor recurrence was observed in mice that received RT only. The expression of CSC markers was significantly reduced following PMT treatment. We demonstrate the development of a system for the precise removal of CSC with good biosafety and high potential for clinical translation. We believe the PMT nanosystem represents a novel idea in the prevention of tumor recurrence.

Recovery of zinc and extraction of calcium and sulfur from zinc-rich gypsum residue by selective reduction roasting combined with hydrolysis.

A novel process that includes selective reduction roasting followed by hydrolysis was proposed in this work to recover zinc, and efficiently extract calcium and sulfur from hazardous zinc-rich gypsum residue (ZGR) waste for high-purity of CaCO3 and sulfur production. The selective reduction behaviors of ZGR during the reduction roasting were investigated in detail based on thermodynamic analysis and roasting experiments. The effect of roasting temperature, carbon dosage and time on the selective reduction of ZGR was comprehensively investigated, and the results indicated that ZnO and CaSO4 in the ZGR can be selectively reduced to Zn(g) and CaS, respectively. The volatile Zn(g) was oxidized to ZnO and enriched in the dust, which can be used as a secondary zinc resource. Moreover, the hydrolysis behaviors and leaching kinetic of CaS during hydrolysis were studied intensively. Results depicted that in the H2S-H2O system, the CaS in the roasted product can be selectively and efficiently dissolved into the leachate. Furthermore, the kinetic analysis revealed that the hydrolysis of CaS conformed to the internal diffusion reaction control model in the shrinking core model and the apparent activation energy Ea = -12.02 kJ/mol. The obtained hydrolysate with low impurities could be used to capture CO2 for the production of high-purity sulfur and CaCO3. Iron and other impurities in the roasted product were concentrated into the leaching slag in the form of metallic iron and akermanite. The whole process realized the recovery of zinc, and the selective and effective extraction of calcium and sulfur, which could provide an alternative process for the large-scale treatment of these hazardous wastes.

Current Self-Healing Binders for Energetic Composite Material Applications.

Energetic composite materials (ECMs) are the basic materials of polymer binder explosives and composite solid propellants, which are mainly composed of explosive crystals and binders. During the manufacturing, storage and use of ECMs, the bonding surface is prone to micro/fine cracks or defects caused by external stimuli such as temperature, humidity and impact, affecting the safety and service of ECMs. Therefore, substantial efforts have been devoted to designing suitable self-healing binders aimed at repairing cracks/defects. This review describes the research progress on self-healing binders for ECMs. The structural designs of these strategies to manipulate macro-molecular and/or supramolecular polymers are discussed in detail, and then the implementation of these strategies on ECMs is discussed. However, the reasonable configuration of robust microstructures and effective dynamic exchange are still challenges. Therefore, the prospects for the development of self-healing binders for ECMs are proposed. These critical insights are emphasized to guide the research on developing novel self-healing binders for ECMs in the future.

Near-Infrared Aggregation-Induced Emission Luminogens for In Vivo Theranostics of Alzheimer's Disease.

Optimized theranostic strategies for Alzheimer's disease (AD) remain almost absent from bench to clinic. Current probes and drugs attempting to prevent ß-amyloid (Aß) fibrosis encounter failures due to the blood-brain barrier (BBB) penetration challenge and blind intervention time window. Herein, we design a near-infrared (NIR) aggregation-induced emission (AIE) probe, DNTPH, via balanced hydrophobicity-hydrophilicity strategy. DNTPH binds selectively to Aß fibrils with a high signal-to-noise ratio. In vivo imaging revealed its excellent BBB permeability and long-term tracking ability with high-performance AD diagnosis. Remarkably, DNTPH exhibits a strong inhibitory effect on Aß fibrosis and promotes fibril disassembly, thereby attenuating Aß-induced neurotoxicity. DNTPH treatment significantly reduced Aß plaques and rescued learning deficits in AD mice. Thus, DNTPH serves as the first AIE in vivo theranostic agent for real-time NIR imaging of Aß plaques and AD therapy simultaneously.

Phase Competition in High-Quality Epitaxial Antiferroelectric PbZrO3 Thin Films.

Antiferroelectric PbZrO3 has attracted renewed interest in recent years because of its unique properties and wide range of potential applications. However, the nature of antiferroelectricity and its evolution with the electric field and temperature remain controversial, mostly due to the difficulty of obtaining high-quality single-crystal samples. The lack of consensus regarding the phase transition in PbZrO3 is not only important on a fundamental side but also greatly hinders further applications. Herein, high-quality PbZrO3 epitaxial thin films are successfully fabricated by pulsed laser deposition. The structural and physical properties of the films are systematically studied via a combination of electric property measurements, X-ray diffraction, scanning transmission electron microscopy imaging, and second-harmonic generation studies. Our studies unveil the noncentrosymmetric nature of PbZrO3 films at room temperature. Moreover, the Curie temperature increased to 270°, ∼40° higher than that in the bulk, and no intermediate ferroelectric phase was observed. Besides, an incipient ferroelectric with relaxor-like behavior above the Curie temperature due to the existence of a local polar cluster in the high-temperature paraelectric phase is experimentally observed for the first time. Our studies provide a better understanding of PbZrO3 thin films and pave the way for practical applications of antiferroelectric material in modern electronic devices.

Molecular logic operations from complex coacervation with aggregation-induced emission characteristics.

Leveraging complex coacervation of a polycation and a bivalent anion with aggregation-induced emission characteristics, we accomplish eight basic logic operations with environmental stimuli as inputs, producing Boolean-like fluorescence intensity or turbidity 'outputs' with contrast higher than one order of magnitude. Storage of information of a fluorescent pattern and thermo-sensor applications are also demonstrated.

Multifaceted Cargo Recruitment and Release from Artificial Membraneless Organelles.

Liquid-liquid phase separation (LLPS) drives membraneless organelles (MLOs) formation for organizing biomolecules. Artificial MLOs (AMLOs) have been constructed mostly via the LLPS of engineered proteins capable of regulating limited types of biomolecules. Here, leveraging a minimalist AMLO, driven by LLPS of polymer-oligopeptide hybrids, enrichment, recruitment, and release of multifaceted cargoes are quantitatively shown, including small fluorescent molecules, fluorophore-containing macromolecules, proteins, DNAs, and RNAs. Cargoes show up to 105 -fold enrichment, whilst recruitment and release are triggered by variations of temperature, pH, and/or ionic strength. Also, the first efficacious, rapid, and reversible control of aggregation-induced emission with over 30 folds of modulation of overall fluorescence intensity is achieved, by intensifying the aggregation of luminogens in AMLO. The AMLO is a simple yet versatile platform for potential drug delivery and biosensor applications.

Safety and efficacy of mutant neoantigen-specific T-cell treatment combined anti-PD-1 therapy in stage IV solid tumors.

Aims: This trial explored the safety and efficacy of neoantigen-specific T cells (Nas-Ts) combined with anti-PD-1 (Nas-T + anti-PD-1). Patients & methods: This non-randomized trial recruited participants with solid tumors treated with at least two prior systemic treatment lines. For comparison, 1:1-matched controls who received anti-PD-1 alone were recruited. The primary end point was safety. Results: 15 participants were enrolled in the Nas-T + anti-PD-1 group, the objective response rate was 33.3%, and the disease control rate was 93.3%. The median progression-free survival was significantly different between the Nas-T + anti-PD-1 and control groups (13.8 vs 4.2 months; p = 0.024), but no difference in overall survival was found (p = 0.126). The most common adverse events were maculopapular skin reaction (53.3%), rash (53.3%), hepatotoxicity (53.3%) and fever (53.3%) in the Nas-T + anti-PD-1 group. No serious safety issues were experienced. Conclusion: Nas-Ts combined with anti-PD-1 could be more effective than anti-PD-1 alone in prolonging progression-free survival, with good safety.

Cancer immune escape is a major mechanism allowing cancer cells to avoid treatments, and PD-1 is one of those mechanisms. Nevertheless, therapies targeting PD-1 are still somewhat unsatisfactory. In this trial, we explored the safety and efficacy of mutant neoantigen-specific T cells (Nas-Ts) as adoptive cell immunotherapy individualized for each tumor, combined with an anti-PD-1 regimen (Nas-T + anti-PD-1). We recruited participants with solid tumors treated with at least two prior systemic treatment lines: 15 participants were enrolled in the Nas-T + anti-PD-1 group and 15 more in the control group. After the last follow-up, the percentage of patients on whom a therapy had some defined effect as well as the percentage of patients with advanced and metastatic cancer who achieved complete response was significantly higher for those who received Nas-T + anti-PD-1. No serious safety issues were experienced. This study confirmed that Nas-Ts combined with anti-PD-1 could be more effective than anti-PD-1 alone in delaying progression, with good safety.